Back to EveryPatent.com
| United States Patent |
6,197,337
|
|
Weisman
, et al.
|
March 6, 2001
|
Therapeutic uses of abarelix
Abstract
A method of decreasing atherosclerosis and its complications including but
not limited to myocardial infarction, stroke and peripheral vascular
disease wherein the method involves administering to a human or an animal
an amount of abarelix sufficient to reduce atherosclerosis and its
complications.
| Inventors:
|
Weisman; Kenneth (30 Springton Point Dr., Newtown Square, PA 19073);
Goldberg; Michael E. (20 Aspen Dr., Ivyland, PA 18974)
|
| Appl. No.:
|
566608 |
| Filed:
|
May 9, 2000 |
| Current U.S. Class: |
424/464; 424/422; 424/449; 424/489 |
| Intern'l Class: |
A61K 009/14; A61K 009/20; A61K 009/70 |
| Field of Search: |
424/464,449,489,422
514/824
|
References Cited
U.S. Patent Documents
| 5574011 | Nov., 1996 | Tien | 514/14.
|
| 5795909 | Aug., 1998 | Shashoua et al. | 514/449.
|
| 5968895 | Oct., 1999 | Gefter et al. | 514/2.
|
Primary Examiner: Page; Thurman K.
Assistant Examiner: Evans; Charesse
Attorney, Agent or Firm: Caesar, Rivise, Bernstein, Cohen & Pokotilow
Parent Case Text
This application claims the benefit of the filing date of May 10, 1999 of
Provisional Patent Applications Serial No. 60/133,481.
Claims
What is claimed is:
1. A method of decreasing atherosclerosis and its complications comprising
administering to a human or animal an amount of abarelix sufficient to
decrease atherosclerosis and its complications.
2. The method in claim 1 wherein the effective amount of abarelix is a 3
mg/kg/month intramuscular injection, administered monthly.
3. The method in claim 1 wherein abarelix is administered as a tablet, or
as a part of a liquid solution or dispersion, or patch, or subcutaneous
pellet, or any other method with the intent of accomplishing systemic
absorption or the drug.
4. The method of claim 1 wherein the complications are selected from the
group consisting of myocardial infarction, stroke and peripheral vascular
disease.
Description
BACKGROUND OF THE INVENTION
There are many steps in the biosynthesis and utilization by the tissues of
testosterone. Testosterone is made mostly in the testicles. A lesser
amount is made in the adrenals. Production is stimulated by secretion of
Gn RH or LHRH by the brain, which causes secretion of luteinizing hormone
(LH) by the pituitary, which causes the testicles to make testosterone.
Testosterone then flows into the blood stream and is absorbed by the
target cells. Here it binds to a receptor and is transported into the cell
and converted to dihydrotestosterone. This is bound and carried to the
nucleus of the cell where it redirects cellular activity by turning on and
off DNA. Hormonal manipulation is a term which refers to the reduction of
testosterone or its effects by blocking any step in the above process in
order to gain a desired effect. Until now the uses of hormonal
manipulation include for example treating prostatic carcinoma, and
treatment for baldness.
The present invention involves the use of hormonal manipulations in the
prevention and treatment of cardiac events, including atherosclerosis,
coronary heart disease, stroke and peripheral vascular disease. We have
already discovered as reflected by our pending patent applications that
certain 5-alpha reductase compounds are effective.
For instance, leuprolide acetate is one of the compounds we previously
discovered being effective in the prevention of such cardiac events.
Leuprolide acetate is a synthetic nonapeptide of naturally occurring
gonadotropin-releasing hormone (GnRH or LH-RH), the chemical name is
5-oxo-L-prolyl-L-histidyl-L-tryptophyl-L-seryl-L-tyrosyl-D-leucyl-L-leucyl
-L-arginyl-N-ethyl-L-prolinamide acetate salt sold under the trade name
Lupron or Lupron Depot, as identified by U.S. Pat. No. 4,897,256, the
entire disclosure is incorporated by reference herein, is known for use in
the treatment of prostatic carcinoma. Leuprolide is a potent inhibitor of
gonadotropin secretion known to decrease levels of LHRH, LH and
Testosterone.
Another compound we previously discovered as being effective in the
prevention of such cardiac events is goserelin acetate, a synthetic
decapeptide analogue of LHRH or GnRH, is chemically described as an
acetate salt of [D-Ser(Bu.sup.t).sup.6 Azygly.sup.10 ] LHRH. Its chemical
structure is pyro-Glu-His-Trp-Ser-Tyr-D-Ser(Bu)-Leu-Arg-Pro-Azgly-NH2
acetate [C59H84N18014 (C2H402) sold under the trade name Zoladex, as
identified by the U.S. Pat. No. 5,510,460, the entire disclosure is
incorporated by reference herein, is known for the use in treatment of
prostatic carcinoma. Goserelin acetate is a potent inhibitor of
gonadotropin secretion known to reduce levels of GnRH or LHRH, LH and
Testosterone.
Finasteride, sold under the trade name Proscar by Merck and Co., is
currently used in the treatment of benign prostatic hyperplasia, and is
known to inhibit testosterone metabolism by blocking conversation of
testosterone to dihydrotestosterone by blocking 5-alpha-reductase.
Finasteride is yet another compound we previously discovered as being
effective in the prevention of cardiac events.
Now, we have discovered the existence of abarelix which is a synthetic LHRH
antagonist, the chemical name is
N-Acetyl-3-(2-naphyl)-D-alanyl-4-chloro-D-phenylalanyl-3-(3-pyridyl)-D-ala
nyl-L-seryl-N-methyl-L-tyrosyl-D-aspaaginyl-L-leucy-N.sup.6
-isopropyl-L-lysyl-L-prolyl-D-alanylamide, manufacturer Praecis
Pharmaceuticals Inc. is known for use in treatment of prostatic carcinoma.
Abarelix is an inhibitor of gonadotropin secretion known to decrease
levels of LHRH, LH, and Testosterone. Based on our studies of other
5-alpha reductase compounds, we believe that abarelix should be effective
in preventing these cardiac events.
One of our studies of other 5-alpha reductase compounds was a retrospective
study involving leuprolide acetate, goserelin acetate and finasteride was
performed which compared the rates of patient reported heart attack in
several groups: 1--control group of males entering the urology office for
any routine complaint. 2--a group of prostate cancer patients treated with
Leuprolide acetate, a LHRH inhibitor. 3--a group of prostate cancer
patients treated with Goserelin acetate (Zoladex), a LHRH inhibitor. 4--a
group of prostate cancer patients not treated with hormonal manipulation
(neither leuprolide acetate or goserelin acetate). 5--a group of patients
treated with finasteride (another form of hormonal manipulation). 6--all
patients on LHRH inhibitors (group 2+group 3).
The patients on either leuprolide acetate or goserelin acetate were treated
with the recommended doses indicated for the treatment of prostatic
carcinoma, at either one or three month intervals depending on the
preparation used. Leuprolide acetate was dosed at 7.5 mg monthly (single
intramuscular injection) or at 22.5 mg at 3 month intervals (single
intramuscular injection). Goserelin acetate was dosed at 3.6 mg monthly
(subcutaneous injection) or at a dose of 10.8 mg at 3 month intervals
(subcutaneous injection).
The various groups of office patients were given a questionnaire. In groups
2, 3 and 5 only those on drug for at least one year were considered.
Cardiac event is defined as either the history of a heart attack or
occurrence of coronary artery bypass or angioplasty. In control groups
only events occurring in the 3 years prior to the questionnaire are
charted. The results were as follows:
Cardiac
No Patients Events Subject Years Events/Year
Group 1 (control 247 26 741 .0351
no cancer)
Group 4 (control 69 6 207 .0290
cancer patients)
Total Control 316 32 948 .0338
(Groups 1 + 4)
Group 2 (lupron 28 1 118 .00847
acetate)
Group 3 25 1 62 .0161
(goserelin
acetate)
Group 5- 91 4 242 .0165
(finasteride)
Group 6 50 2 180 .0111
(antiLHRH)
groups 2 + 3
The observed difference between the proportions of Total Control vs Group 6
(LHRH) is 0.0226. 95% Confidence Interval for the difference between the
proportions is 0.00350 to 0.0418. Patients treated with LHRH inhibitors
had fewer heart attacks than controls.
The observed difference between the proportions of Group 2 (lupron acetate)
and Total Control is 0.0253. 95% Confidence Interval for the difference
between the proportions is 0.00514 and 0.0454. Patients treated with
leuprolide acetate had fewer heart attacks than controls.
The observed difference between the proportions of Group 3 and Total
Control is 0.0177. Patients treated with goserelin acetate (Zoladex) had
fewer heart attacks than controls.
The observed difference between the proportions of Group 1 (Control) and
Group 5 (finasteride) is 0.0186. 90% Confidence Interval for the
difference between the proportions is 0.00103 to 0.0361. Patients treated
with finasteride had fewer heart attacks than control.
It is believed that the use of abarelix will yield similar results.
The foregoing data demonstrates that by inhibiting testosterone metabolism
atherosclerosis and cardiac events can be reduced. This has been
demonstrated at two separate steps in the pathway, both by inhibiting LHRH
and by inhibiting 5-alpha-reductase. Since abarelix acts to inhibit
formation of LHRH it is believed that the use of abarelix will also result
in a reduction of atherosclerosis and its complications; myocardial
infarction, stroke, and peripheral vascular disease.
Without further elaboration the foregoing will so fully illustrate our
invention that others may, by applying current and future knowledge, adopt
the same for use under various conditions of service.
Top